Dual epigenetic changes in diabetes mellitus-associated pancreatic ductal adenocarcinoma correlate with downregulation of E-cadherin and worsened prognosis

Q: What dual epigenetic changes are investigated in diabetes-associated PDAC?

The study examines CDH1 promoter methylation and microRNA changes, specifically miR-100-5p, in relation to E-cadherin and downstream signaling in PDAC.

Q: How were DM-related biomarkers measured in PDAC specimens?

E-cadherin and nuclear β-catenin were assessed by immunohistochemistry, while DNA methylation and miR-100-5p expression were analyzed from formalin-fixed paraffin-embedded tumor sections using methylation-specific PCR and TaqMan miR assays.

Q: How does dual epigenetic alteration affect prognosis in PDAC patients with DM?

PDAC cases showing both high miR-100-5p expression and CDH1 promoter methylation have poorer overall survival and disease-free survival than those with only a single epigenetic change, and miR-100-5p plus CDH1 methylation independently predict worse outcomes.

Sep 28, 2026

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Diabetes mellitus (DM) is evaluated as a driver of dual epigenetic alterations in pancreatic ductal adenocarcinoma (PDAC), focusing on CDH1 promoter methylation and microRNA-mediated regulation of E-cadherin. In 132 radical resection cases, immunohistochemistry quantified E-cadherin and nuclear β-catenin, while miR-100-5p and DNA methylation were measured from tumor tissue. Decreased E-cadherin and increased nuclear β-catenin associate with DM and poor differentiation. Long-duration DM (≥3 years) links to CDH1 promoter methylation, and miR-100-5p tracks preoperative HbA1c. Dual epigenetic changes predict worse OS and DFS, with miR-100-5p ≥4.13 and CDH1 methylation independently prognostic.

LanguageEnglish

CategoryHealthcare

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Pages13

Reading Time33 min

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Abstract

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Introduction

The Journal of Pathology: Clinical Research J Pathol Clin Res September 2023; 9: 354–366 Published online 28 May 2023 in Wiley Online Library (wi[leyonlinelibrary.com](leyonlinelibrary.com). DOI: 10.1002/cjp2.326)[).](leyonlinelibrary.com). DOI: 10.1002/cjp2.326)[ DOI: 10.1002/cjp2.326](leyonlinelibrary.com). DOI: 10.1002/cjp2.326) ORIGINAL ARTICLE Dual epigenetic changes in diabetes mellitus-associated pancreatic ductal adenocarcinoma correlate with downregulation of E-cadherin and worsened prognosis Yutaro Hara 1,2, Hiroki Mizukami 1 * , Keisuke Yamazaki 1,2, Takahiro Yamada 1,2, Akiko Igawa 1,2, Yuki Takeuchi 1 , Takanori Sasaki 1 , Hanae Kushibiki 1 , Kotaro Murakami 1 , Kazuhiro Kudoh 1 , Keinosuke Ishido2 and Kenichi Hakamada2 1 Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan 2Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan *Correspondence to: Hiroki Mizukami, Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. E-mail: [hirokim@hirosaki-u.ac.jp](hirokim@hirosaki-u.ac.jp) Abstract Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of CDH1. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR-100-5p is known to be changed in DM patients and can suppress the expression of E-cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E-cadherin and nuclear β-catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin-ﬁxedparafﬁn-embedded tissue sections. TaqMan miR assays were applied to assess miR-100-5p expression. Bisulﬁte modiﬁcation was conducted on the extracted DNA, which was then subjected to methylation-speciﬁc polymerase chain reaction. Immunohistochemistry revealed that decreased E-cadherin expression and increased nuclear β-catenin expression were signiﬁcantly associated with DM and poor tumor cell differentiation. The presence of long-duration DM (≥3 years) was a signiﬁcant factor contributing to CDH1 promoter methylation (p < 0.01), while miR-100-5p expression was proportionally correlated with the preoperative HbA1c level (R = 0.34, p < 0.01), but not the duration of DM. The subjects with high miR-100-5p expression and CDH1 promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR-100-5p expression ≥4.13 and CDH1 promoter methylation independently predicted poor OS and disease-free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis. Keywords: diabetes mellitus; pancreatic ductal adenocarcinoma; promoter methylation; microRNA; E-cadherin Received 5 December 2022; Revised 2 April 2023; Accepted 4 May 2023 No conﬂicts of interest were declared. Introduction Pancreatic ductal adenocarcinoma (PDAC) remains an intractable cancer with a poor prognosis. The 5-year survival rate of PDAC is low at approximately 10%[1] . Systemic treatment in addition to local control is clearly essential to curing PDAC, while surgical resection of PDAC is still a predominant treatment option. Genetic studies have identiﬁed mutations of four key genes, including KRAS, TP53, SMAD4, and CDKN2A, as responsible for the development of P

FAQs

What dual epigenetic changes are investigated in diabetes-associated PDAC?

The study examines CDH1 promoter methylation and microRNA changes, specifically miR-100-5p, in relation to E-cadherin and downstream signaling in PDAC.

How were DM-related biomarkers measured in PDAC specimens?

E-cadherin and nuclear β-catenin were assessed by immunohistochemistry, while DNA methylation and miR-100-5p expression were analyzed from formalin-fixed paraffin-embedded tumor sections using methylation-specific PCR and TaqMan miR assays.

How does dual epigenetic alteration affect prognosis in PDAC patients with DM?

PDAC cases showing both high miR-100-5p expression and CDH1 promoter methylation have poorer overall survival and disease-free survival than those with only a single epigenetic change, and miR-100-5p plus CDH1 methylation independently predict worse outcomes.

Sep 28, 2026

Uploaded by Angel